Vitamins are considered an essential part of our dietary intake due to the fact that they do play a vital role in keeping the human cells to perform their biochemical functions in order to avoid emergence of a disease process. Hence, vitamins are mostly found in the food that we eat everyday. But there is one type of vitamin that is more than just a supplement and that is vitamin D. Vitamin D is a lipid -soluble vitamin but it is not a pure vitamin because the body's requirement is achieved not only through dietary intake but it is also produced or synthesise by the skin through sun exposure, thus named as the sunshine vitamin.
Vitamin D is now considered a steroid hormone, and to be more specific it is considered as a prohormone which will undergo series of enzymatic activation before instigating effect in mineral homeostasis (Jacobs, M. 1979).
Synthesis and Metabolism
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To fully understand the endocrine function of vitamin D, it is vital to know how vitamin D is produced and processed in the body. Vitamin D is found to be available in a wide range of food stuffs, they maybe in the form of ergocalciferol (vitamin D2) that can be found in margarines and milk, or it may be in the form of cholecalciferols (vitamin D3) in which fish oils are found to be the richest source. These two forms of vitamin D are the same in most aspects, particularly in their metabolism and action. Both of these two forms remained biologically inactive until they have been hydroxylated (Marshall, W. and Bargert, S. 2008). Dietary cholesterol is acted upon by small amount of intestinal enzyme called mucosal dehydrogenase to convert it into 7-dehydrocholesterol that is then transported to the skin. Upon the action of sunlight or ultraviolet radiation with a wavelength of 290 to 320nm, the C9-C10 bond of the provitamin D3 is then broken down to form the previtamin D3 or calciferol. This previtamin D3 form will undergo further reactions and is then released into the circulation. Once in circulation, the calciferol is bound to a protein called vitamin D binding protein and is transported to liver and kidney (Kaplan, A. et al, 2003).
In the liver, the first step of metabolic activation of vitamin D takes place through the hydroxylation of carbon 25 (Dusso, A. et al, 2004) through the action of liver enzyme CYP2R1 in order to produce 25-hydroxyvitamin D (25(OH)D) also known as calcidiol (Cundy, T. et al, 2008) and is then released into the circulation prior to reaching the kidney. In the kidney, the final step of activation takes place, where 25 (OH) D undergoes 1Î± hydroxylation to form 1, 25-dihydrovitamin D3 or calcitriol- the hormonal form of the vitamin, or to produce 24-hydroxylation to form 24, 25 dihydroxyvitamin D (24, 25-(OH) 2D) whose main function in mineral and vitamin D homeostasis is not well known (Kaplan, A. et al, 2003).
Figure 1- schematic diagram of vitamin D synthesis and metabolism.
(Taken from Clinical Biochemistry-Metabolic and Clinical Aspects, 2008)
Vitamin D is considered as one of the major hormones that controls the calcium and phosphorous homeostasis and bone mineralization, and just like other hormones, its activated form is regulated and controlled by feedback regulation (Kaplan, A. et al, 2003).
Vitamin D Receptor
In light of the recent advances in vitamin D studies, the discovery of the vitamin D receptor in many cell types apart from the known tissue targets of kidney, small intestine and bone in the homeostasis of calcium and other minerals has led to the belief that indeed vitamin D has other biological functions(Samuel S. and Sitrin M. 2008).
Vitamin D receptor (VDR) is a member of class II steroid hormone, belonging to the family of steroid-retinoid-thyroid hormone-vitamin D receptor group. It interacts with the retinoic acid X receptor (RXR) in order to form the heterodynamic complex, RXR-VDR to bind with specific DNA known as vitamin D response element or VDRE (Ginanjar, E. et al, 2007). Vitamin D receptor elements have been found in various genes that are involved in many fundamental cell process thereby identifying noncalcemic action of vitamin D and how it affects carcinogenesis, immune function, autoimmune diseases and cardiovascular disorders through its ability to inhibit cellular proliferation. Vitamin D has been shown in a highly cell-specific manner, to distort or alter cell proliferation through various mechanisms, particularly its significant effect on cell cycle progression, differentiation and apoptosis. In most cases the ligand activated VDR directly provide or prohibit the transcription of the key genes that regulates cell growth (Samuel, S. and Sitrin, M. 2008).
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Figure 2-Diagrammatic representation of the known molecular events in the regulation of gene expression by the vitamin D hormone, 1, 25(OH) 2D3, acting through its receptor, VDR. The result of regulation may be either suppression or activation. RXR, retinoidXreceptor; DRE,VDRE(see Figure 5); TFIIB,transcription factor IIB; TFIID, transcription factor IID; RNAP, RNA polymerase. (Taken from Am J Clin Nutr , 2004)
Non Classical Role of Vitamin D
As previously mentioned, vitamin D does have other functions other the classical role of maintaining calcium homeostasis and the skeletal system. Listed below are brief discussions of noncalcemic functions of vitamin D.
Cell growth suppression
Studies have shown that 1,25(OH)2D suppresses clonal proliferation of different leukaemic cell varieties in human. But on the other hand, it was shown that 1,25(OH)D stimulates normal cell differentiation and in return affect cell maturation thereby rendering it to be less aggressive. The antiproliferative action of vitamin D is more autocrine rather than endocrine in nature (Ginanjar, E. et al, 2007). Ginanjar et al (2007) states that, "the underlying mechanism for the hypothesis is by linking 1,25(OD)2D-VDR system that blocks cancer cell cycle in the transition between G1-G0 through several pathways such as:
1. 1,25(OH)2D induces cyclin -dependent kinase inhibitor p21 gene transcription in a way that it inhibits cancer cell growth and stimulates monocytes -macrophage cell differentiation.
2. 1,25(OH)2D induces the synthesis and or stabilization of cyclin-dependent kinase p27, which prevents proteosomal degradation.
3. In tumours which growth are regulated by over expression of TGF-Î±/EGFR, 1,25(OH)2D inhibits growth signal of EGFR on the cell membrane and inhibits transactivation of cyclin D1 gene from EFGR at the nucleus. This is the evidence that vitamin D has the potential as therapy for hyperplastic keratinocyte growth in psoriasis patients.
4. In HL60 cell line monocytes and in osteoblast , 1,25(OH)2D induces the expression of C/EBPÎ², a protein that is currently believed to have potential as a suppressor of oncogenic -cyclin D1in epithelial tumour.
5. 1,25(OH)2D reduces HRPA20 level, a phospho protein that maintains growth and endurance of prolactin-dependent rat Nb2T lymphoma, a tumour that is greatly affected by hormonal factor."
In many cell types, 1,25(OH)2D has been shown to in promote or induce apoptosis by altering the content of various bcl-2 family apoptotic regulatory effect (Samuel, S. and Sitrin, M 2008). " Vitamin D affects the levels of pro-apoptotic (bax, bak)and/or anti-apoptotic (bcl-2, bcl-XL) proteins, thereby tipping the balance toward apoptosis rather than cell survival" (Samuel, S. and Sitrin, M. 2008). But an opposite effect is found on the skin, wherein 1,25(OH)2D protects the keratinocyte from apoptosis as induced by UV light exposure or chemotherapy (Ginanjar, E. et al, 2007).
Regulation of skin function and differentiation
Many studies have shown multiple mechanisms by which 1,25-dihydroxyvitamin D promotes and regulates differentiation of keratinocytes. Calcitriol plays a vital role in expressing CaSR which is central to the regulation of keratinocyte differentiation by calcium. Also, 1,25-dihydroxyvitamin D induces phospholipase C, and some studies shown to acutely stimulate phosphoinositide turnover, producing an increased intracellular IP3,diacylglycerol, and intracellular calcium levels. All of these changes, along with activation of AP-1 transcription factors lead to induction of multiple genes involved in differentiation, including involucrin, loricin, transglutaminase, and others. The transcriptional profiling of calcitriol-treated keratinocytes has shown induction or suppression of various genes involved in various stages of keratinocyte differentiation, formation of cornified layers, and desquamation. And as keratinocyte differentiation progresses, changes in the expression and function of VDR co activators have been observed, and is likely contributing to the temporal sequence of vitamin D-mediated gene expression during differentiation (Samuel, S. and Sitrin, M. 2008).
Regulation of renin-angiotensin system
The renin-angiotensin system is the hormone system that regulates the blood pressure, electrolyte and water or volume homeostasis. In several clinical and epidemiological studies, it has established the association between inadequate sunlight exposure and low serum level of 1,25(OH)2D with high blood pressure and high plasma renin activity. In a study done on VDR-null mice, it has shown that marked increased in renin expression and plasma angiotensin II production will cause hypertension, cardiac hypertrophy and increased water intake (Dusso, A. et al, 2004)
Control of Insulin secretion
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Studies have shown the biological evidence implicating a potential influence of vitamin D on glucose homeostasis. The influencing role of vitamin D includes the presence of specific vitamin D receptors(VDRs) on pancreatic Î²-cells , the expression of 1-Î±-hydroxylase enzyme in pancreatic Î²-cells which catalyzes the conversion of 25(OH)D to 1,dihydroxyvitamin D(1, 25(OH)2D) , the presence of a vitamin D response element in the human insulin gene promoter , and the presence of VDR in skeletal muscle. Also 1, 25(OH)2D directly activates transcription of the human insulin receptor gene ,as well as activates peroxisome proliferators activator receptor-Î´ , and stimulates the expression of insulin receptor, and enhances insulin-mediated glucose transport in vitro (Alvarez, J and Ashraf, A. 2008).
Control of muscle function
Patients suffering from chronic renal failure or on a long term use of anticonvulsant drugs will experience muscle weakness and atrophy together with electrophysiological disturbance in muscle contraction and relaxation mechanism due to vitamin D deficiency as an after effect of the above mentioned conditions. And though these were attributed to low levels of calcium, there is evidence of direct 1,25 (OH) 2D actions on the skeletal muscle growth and differentiation in VDR-null mice study.
In heart conditions, 1,25(OH)2D prevents myocardial hypertrophy of the cardiac muscles and facilitate the synthesis and release of atrial natriuretic factor. In chronic renal failure, supplementation of Vitamin D improves both left ventricular functions in patients with cardiomyopathies and muscle weakness (Dusso, A. et al., 2004).
Control of nervous system
The action of 1,25(OH)2D in the nervous system include induction of the VDR content (as VDR is expressed in the brain and in other region of the central and peripheral nervous system), the conductance velocity of the motor neurons as well as the synthesis of neurotrophic factors like the nerve growth factors and the neurotrophyns which prevent the loss of injured neurons. It also enhances the expression of the glial cell line-derived neurotrophic factor which is potentially a candidate for treatment of Parkinson's disease (Dusso, A. et al, 2004).
In a study done on embryonic rat brain, low levels of prenatal vitamin D shows increased in brain size , altered brain shape , enlarged ventricles and there is a reduction in nerve growth factor expression. The association between deficiency in vitamin D and abnormal brain development makes it a potential candidate in the treatment of schizophrenia, a disorder resulting from gene-environment interactions that disrupt brain development (Dusso, A. et al, 2004).
Vitamin D and autoimmune disease
As in most cell types, vitamin D receptor is found in significant concentrations in the T lymphocytes and macrophages populations, although the highest concentration is in the immature cells of the thymus and the mature CD-8 T lymphocytes. The vital or important role vitamin D compounds as selective immunosuppressant is shown by their ability to prevent or significantly suppress animal models of autoimmune disease. The results show that 1,25 (OH)2D can either prevent or suppress experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease. In most cases, the action of vitamin D hormone necessitates the need for a high calcium diet amongst the animal model. Possible suppressive mechanism of these autoimmune disorders on the vitamin D hormone has been presented (Deluca, H. and Cantorna, M. 2001). Deluca and Cantorna (2001) states that "the vitamin D hormone stimulates transforming growth factor TGFÎ²-1 and interleukin 4 (IL-4) production which in turn may suppress inflammatory T cell activity."
It is noteworthy to realise that vitamin D does not appear to have an effect on B lymphocytes due to the fact that B lymphocyte does not contain VDR in appreciable amount. (Deluca, H. and Cantorna M. 2001).
The suppression of autoimmune disease does not only rely on the active form of vitamin D and its analogs, but also to adequate or high calcium intake (Deluca, H. and Cantorna, M. 2001).
Vitamin D and immune response
Ginanjar et al (2007) states that "there is a cause and effect relationship between 1,25 (OH)2D-VDR function and immunity to infection, wherein vitamin D deficient patients often experience reinfection and become worse, for example in Rickets and compromised immune system in chronic renal failure with vitamin D deficiency. Altered VDR function as a result of certain VDR allele expression, influences the acceptance of mycobacteria or viral infection. 1,25(OH)2D also function as adjuvant to vaccine, the mechanism is by 1,25(OH)2D inducing p21 and C/EBPÎ² that could mediate the increase of macrophage and monocyte immune function."
Assessment of Vitamin D status
In view of the vast presence of vitamin D in most cell type, it is but only proper to have a reliable and tested laboratory assay that will detect and measure presence of vitamin D, particularly 1,25(OH)2D. 1, 25(OH)2D concentrations are considered the best measure of vitamin D status but commercially available assays for 1,25(OH)2D yielded widely differing results. Therefore, it is very important to develop a standard and highly reliable 25(OH)D assay before supplementation levels can be set on the basis of serum 25(OH)2D concentrations. It has been established that, when large amounts of vitamin D are given to a patient, most of the vitamin D is stored in adipose tissues. When these sites have been saturated, the vitamin D remains in serum and is converted to 25(OH)D3, which is toxic as an analog of 1,25(OH)2D. If the dietary levels of vitamin D needed to achieve normal concentrations of 25(OH)D3 in the plasma are being determined, vitamin D3 itself should be measured, to confirm that vitamin D3is not being accumulated to an extent that would result in vitamin D intoxication. These measurements with well-established, precise methods, together with a careful, clinical, dose-escalation study, should allow setting of a supplementation level that is safe and can help prevent degenerative diseases, as well as preventing or reducing the risk of autoimmune diseases (Deluca, H. 2004).
The discovery of the vitamin D receptor (VDR) has opened new avenues to explore in terms of the biological functions of vitamin D as an endocrine system. Studies done on VDR-null mice have established that indeed vitamin D as a hormone does not only regulate the calcium and other mineral homeostasis as well as bone development but also have noncalcemic effect on various conditions such as cancer, cardiovascular disease, autoimmune disease and other immune response through its feedback mechanism. To this day, the exact mechanism as to how vitamin D deficiency and its subsequent supplementation affect various noncalcemic conditions still remain an area of much interest and study.